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The analgesic action of 5-HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C-fibre-evoked field potentials (FPs) in spinal long-term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model. C-fibre-evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high-frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection. Milnacipran produced prolonged inhibition of C-fibre-evoked FPs when applied spinally after the establishment of LTP of C-fibre-evoked FPs in naïve animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C-fibre-evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5-HT½ receptor antagonist, and yohimbine or idazoxan, α₂-adrenoceptor antagonists. However, spinal administration of milnacipran in naïve animals did not affect the basal C-fibre-evoked FPs and the induction of spinal LTP. Milnacipran inhibited C-fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5-hydroxytryptaminergic and noradrenergic systems. The condition-dependent inhibition of the C-fibre-mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Citation

S Ohnami, A Kato, K Ogawa, S Shinohara, H Ono, M Tanabe. Effects of milnacipran, a 5-HT and noradrenaline reuptake inhibitor, on C-fibre-evoked field potentials in spinal long-term potentiation and neuropathic pain. British journal of pharmacology. 2012 Oct;167(3):537-47

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PMID: 22537101

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